Structural Biochemistry/Enzyme Regulation/Acetylation

Acetylation introduces an acetyl group to a molecule. More specifically, the reaction replaces a hydrogen from an alcohol group with an acetyl. An example is the synthesis of aspirin from salicylic acid:

Aspirin synthesis

Acetylation is an important post-translational protein modification and regulation. An example is the acetylation/deacetylation of histone which subsequently express/inhibit genes since histone binds to DNA itself. Histone Acetyltransferase catalyzes the acetylation of lysine from the histone tail with an acetyl group from Acetyl CoA.

The acetylation of lysine in histone removes the positive charged ammonium group and renders the side chain neutral, which decreases the histone tail affinity for DNA and loosens the histone complex.

The now-acetylated histone can interact with an acetyllysine-binding domain in many eukaryotic proteins called w:bromodomain, an 110 amino acids protein with a four-helix bundle and a peptide-binding site at one end.

Acetylation is the reaction in which an acetyl functional group is added to an organic molecule. In proteins, an acetyl group to either added to the N-terminus of proteins and at lysine residues as a post-translational protein modification.

N-alpha-Terminal Acetylation

The role of N-alpha-Terminal Acetylation is still relatively unknown and under research. However, it is known that this modification is actually widely prevalent in eukaryotes and yeast, though uncommon in prokaryotes, and is performed by a subgroup of acetlytransferases known as N-alpha-acetyltransferases (NATs). There are three major NATs (A,B,C) which perform the majority of the N-alpha-terminal acetylations of eukaryotes The reaction is begun with the cleaving of N-terminal methionine residues with small side chains containing, glycine, alanine, serine, cysteine, threonine, proline, and valine, by methionine aminopeptidases (MAP), Map1p and Map2p. Subsequently, the NATs recognize and acetylate specific sequences of the cleaved proteins.

Lysine Acetylation

One major area in which lysine acetylation is prevalent is in the acetylation of histones, which is performed by histone acetyltransferases (HATs) and deacetylases (HDACs). In both acetylation and deacetylation reactions that attach to the NH3+ tail from an acetyl group from Acetyl-Coenzyme A and remove the acetyl group from lysine onto Coenzyme A, respectively. The acetylation and deacetlyation of histones partake in gene regulation. Histones are packages of strongly alkaline protein around which DNA is wound to allow DNA to be stored in an orderly fashion. Since the acetylation occurs at the NH3+ tail of lysine, the charge of the protein is affected. When acetylated, the positive charge of lysine is eliminated. This decreases the histones affinity to the negatively charged DNA strand, thereby loosening the strand, and the reverse results occur with deacetylation. However, Lysine acetylation isn’t limited to histone acetylation. Among other things, it is also involved in the modification and regulation of non-histones such as cytoplasmic enzymes and p35, a tumor suppressor and involved with signal transmittance and signaling.

Many of the drugs used today for common diseases require additional structuring in order for efficient metabolism in the body. Drugs that are significantly metabolized by acetylation include isoniazid, hydralazine, procainamide, phenelzine, and dapsone that are used to treat tuberculosis, cardiac failure/hypertension, ventricular arrhythmias, depression, and leprosy/skin infections respectively.